Virus-like particle vaccine targeting meningeal lymphatic vessels via intradural delivery activates anti-glioma immunity.

BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor with a poor prognosis, largely due to an immunosuppressive microenvironment and the blood-brain barrier. The discovery of meningeal lymphatic vessels (MLVs) offers a new avenue for central nervous system immune engagement. OBJECTIVE: We aimed to develop a novel immunotherapy by combining a virus-like particle (VLP) nanovaccine with intradural administration to activate meningeal immunity against GBM. METHODS: A virus-like particle (VLP)-based nanovaccine (OVA-HBc) was engineered and characterized. Its efficacy was evaluated in an orthotopic GL261-OVA-Luc glioma mouse model, comparing intradural delivery with intravenous and intranasal routes through tumor imaging and survival analysis. RESULTS: OVA-HBc formed stable nanoparticles (~ 36 nm), was non-toxic, and potently activated dendritic cells in vitro. In vivo, only intradural administration of OVA-HBc induced marked tumor regression and was associated with prolonged survival (over 60% survival at 60 days), showing potential advantages over systemic routes. This effect is likely mediated by precise meningeal targeting and efficient antigen drainage via MLVs. CONCLUSION: This study suggests that intradural delivery of HBc VLPs can engage MLVs to activate anti-glioma immunity in a mouse model. This approach offers a potential strategy to bypass certain central delivery barriers, representing a preliminary framework for GBM immunotherapy.